Increasing the amount of naturally occurring chemicals in the body known as endocannabinoids might help counteract the addictive qualities of opioids, such as morphine and oxycodone, while still allowing these drugs to effectively manage pain, suggests a new study conducted by investigators from Weill Cornell Medicine in collaboration with researchers from The Center for Youth Mental Health at NewYork-Presbyterian. Endocannabinoids interact with cannabinoid receptors distributed throughout the body, influencing various functions including learning, memory, emotions, sleep, immune response, and appetite.
A study by Weill Cornell Medicine scientists, in association with The Center for Youth Mental Health at NewYork-Presbyterian, indicates that raising levels of naturally occurring body chemicals called endocannabinoids may help reduce the addictive tendencies of opioids like morphine and oxycodone while still preserving the pain relief these drugs provide. Endocannabinoids connect with cannabinoid receptors located throughout the body, which oversee many functions, including learning, memory, emotional regulation, sleep, immune system responses, and appetite.
Opioids, commonly prescribed for pain management, can lead to addiction not only due to their pain-relieving properties but also because they evoke feelings of euphoria. This preclinical study, published on November 29 in Science Advances, may pave the way for a new type of treatment that could be administered alongside opioids, potentially diminishing their rewarding effects.
In 2023, opioid misuse was linked to over 80,000 deaths, contributing to a national crisis as per the U.S. Centers for Disease Control and Prevention. While many overdoses involved illegally obtained substances, that’s not the full story. “Post-surgery patients using opioids for pain management face a constant risk of becoming dependent on these medications,” explained senior author Dr. Francis Lee, chair of the Department of Psychiatry at Weill Cornell Medicine and psychiatrist-in-chief at New York-Presbyterian/Weill Cornell Medical Center.
Co-senior author Dr. Anjali Rajadhyaksha, an adjunct professor of neuroscience research in pediatrics at Weill Cornell and director of the Center for Substance Abuse Research at the Lewis Katz School of Medicine at Temple University, along with Dr. Arlene Martinez-Rivera, who was the lead author and an instructor in Dr. Rajadhyaksha’s lab during the study—now an assistant professor at the Katz School of Medicine—played key roles in this research.
A Different Perspective
The research team wasn’t originally focused on opioids. Dr. Lee was exploring endocannabinoids’ roles in regulating fear and anxiety, while Dr. Rajadhyaksha was investigating cocaine addiction in mouse models. They teamed up after finding literature suggesting a possible interaction between the opioid system and the endocannabinoid system’s intricate network.
Both opioids and endocannabinoids trigger the brain’s reward system to release dopamine, with substances like tetrahydrocannabinol (THC) from marijuana producing similar euphoric effects. However, while they operate on cannabinoid receptors, opioids engage different receptors.
Interestingly, their results challenge the widespread belief that combining endocannabinoids and opioids would heighten addictive behaviors. “Given that neither of us was deeply embedded in opioid research, we stumbled upon the intriguing idea that one system might actually inhibit the other’s reward effects,” Dr. Lee noted, who also serves as a professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
Surprising Interaction of Reward Systems
Building on this hypothesis, Dr. Martinez-Rivera began experimenting with increasing the levels of the two principal endocannabinoids—anandamide (AEA) and 2-AG—in mice. “We encountered many initial setbacks while testing AEA and nearly decided to abandon the project,” she admitted. “However, after shifting our focus to 2-AG, we began to see promising results.” By raising the levels of 2-AG, the study was able to diminish the rewarding effects of opioids, effectively reducing behaviors linked to opioid addiction, while still providing pain relief in their mouse model.
The researchers utilized a compound named JZL184, which inhibits the breakdown of 2-AG, thus raising its levels within the brain. Their evaluations demonstrated diminished addictive behavior in mice that received a low dose of JZL184 prior to morphine or oxycodone administration.
Additionally, in pain assessments, the mice that received JZL184 displayed noticeable pain relief effects from morphine and oxycodone. “This indicates that endocannabinoids and opioids may not collaborate in the brain and spinal cord areas responsible for pain relief,” Dr. Rajadhyaksha explained. “Conversely, their interaction appears to occur in brain regions that play a role in reducing reward and dependency.”
Follow-up tests indicated that 2-AG achieves its impact by acting through the CB1 cannabinoid receptor in the ventral tegmental area, a neuron group in the midbrain significant for motivation and reward. Boosting 2-AG levels also lowered dopamine signaling, a vital component of the reward system.
“This serves as one of the earliest examples demonstrating that activating the endocannabinoid system can counteract another reward system—in this particular case, the opioid system,” remarked Dr. Rajadhyaksha.
Potential drugs like JZL184 are currently undergoing clinical trials as possible therapies for anxiety disorders, and Dr. Lee is hopeful about the prospects of testing these alongside opioids for pain management in humans. “We’re approaching this with care and striving to translate these findings from preclinical stages to real-world applications that can benefit patients,” Dr. Lee said.
